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A kind of monofunctional branched polyethylene glycol

A polyethylene glycol and functionalization technology, applied in the field of polymer synthesis, can solve the problems of large molecular weight, end group modification rate (substitution rate, limited functionalization rate, large steric hindrance, etc.

Active Publication Date: 2021-05-28
XIAMEN SINOPEG BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the above preparation method, a single reactive group succinimide active ester is obtained by modifying the terminal carboxyl group in the last step. The modification rate (substitution rate, functionalization rate) of the end group is limited due to factors such as large resistance; and because the molecular weight before and after the modification of the end group is large and close, it also brings difficulties to the separation and purification of the product

Method used

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  • A kind of monofunctional branched polyethylene glycol
  • A kind of monofunctional branched polyethylene glycol
  • A kind of monofunctional branched polyethylene glycol

Examples

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preparation example Construction

[0404] Typical examples of the branched polyethylene glycol structure obtainable by the preparation method of the present invention are as follows and any structure in which the functional end group is protected. The aldehyde group, amino group, azido group and maleimide group can be replaced by other suitable functional groups applicable to the preparation method of the present invention.

[0405] A preferred mPEG molecular weight is selected from 2kDa-20kDa; more preferably 2kDa, 5kDa, 10kDa or 20kDa.

[0406] In one preferred mPEG, the number of oxyethylene units is selected from 2-70; preferably 2-20.

[0407] Among them, R 22 selected from –CH 3 , –CH(CH 3 ) 2 , –CH 2 CH(CH 3 ) 2 , –CH(CH 3 )–CH 2 CH 3 , –Bn, –CH 2 CH 2 –SCH 3 , more preferably methyl; wherein, p is an integer greater than 1; preferably an integer of 1-16.

[0408] Among them, R 20 Preferably H atom or R 22 .

[0409]

[0410]

[0411]

[0412]

[0413]

[0414] 4. Equivale...

Embodiment 1

[0445] Embodiment 1 branched polyethylene glycol propionaldehyde

[0446] The branched polyethylene glycol propionaldehyde with a molecular weight of about 40 kDa was prepared by using functionalized polyethylene glycol monomethyl ether with a molecular weight of 20 kDa as a raw material.

[0447] (1) Branched polyethylene glycol propionaldehyde with asymmetric structure (the linking group between the two PEG components and the N branching center is different)

[0448]

[0449] Corresponding to general formula (1), where, L a , L b is methylene, L 2 is carbonyl, L c is methylene, L d is an amide bond (-CONH-), wherein, Z is methylene, and F is -CHO. Design two mPEG(CH 3 O(CH 2 CH 2 O) n -) The molecular weight is about 20kDa.

[0450] The preparation process is as follows:

[0451] Step a: Dissolve 10g (47.8mmol) of benzyloxycarbonyl-protected glycine (S1-1) in dichloromethane, add 6.5g (57mmol) of N-hydroxysuccinimide (NHS) and stir to dissolve, then add to the ...

Embodiment 2

[0467] Embodiment 2 branched polyethylene glycol propionaldehyde (one-step coupling method)

[0468]

[0469] Corresponding to general formula (1), where, L a , L b is methylene, L 2 is methylene, L c is methylene, L d is an amide bond (-CONH-), wherein, Z is methylene, and F is -CHO. Both mPEGs were designed to have a molecular weight of approximately 10 kDa.

[0470] The preparation process is as follows:

[0471] Steps a~b: Repeat steps a~b in Example 1(1). The amino acetal intermediate S1-3 (7.3 g, yield 92%) was obtained.

[0472] Step c: Using the preparation method of Example 1 (1) step c, using 10kDa, PDI = 1.01 methoxypolyethylene glycol as a raw material to obtain about 44g of methoxypolyethylene glycol mesylate mPEG-OMs .

[0473] Using the alkylation conditions of Example 1 (1) step c, 2mmol of amino acetal intermediate S1-3 and excess methoxypolyethylene glycol methanesulfonate (8mmol) undergo alkylation reaction, membrane filtration, Drying, concentr...

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Abstract

The invention discloses a single functionalized branched polyethylene glycol, the structure of which is shown in the general formula (1), containing two alkoxy-terminated polyethylene glycol branched chains, L a , L b are the same or different divalent linking groups, L 2 is methylene, carbonyl or thiocarbonyl, L c is the carbon chain linking group, L d It is a divalent linking group and contains a covalent bond generated by a coupling reaction, Z does not exist or is any suitable divalent linking group, and F is a functional end group such as an aldehyde group. The monofunctional branched polyethylene glycol of the present invention has a relatively high end group substitution rate, which is greater than 95%, and can reach as high as 99% to 100%. It can be used to produce high-performance pegylated drugs.

Description

technical field [0001] The invention relates to the field of polymer synthesis, in particular to a monofunctional branched polyethylene glycol. Background technique [0002] PEGylation is one of the important means of drug modification. Among them, functionalized polyethylene glycol (PEG) can use its active groups to interact with drug molecules (including protein drugs and organic small molecule drugs), peptides, sugars, lipids, oligonucleotides, affinity ligands, etc. Coupling of body, cofactor, liposome and biomaterials through covalent bonds to achieve PEGylation of drugs and other biologically related substances. The modified drug molecules will have many excellent properties of polyethylene glycol, such as hydrophilicity, flexibility, anticoagulation and so on. In addition, due to the steric repulsion effect, PEG-modified drugs can avoid glomerular filtration and biological reactions such as immune responses, making them have a longer half-life in the blood than unmo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G81/00C08G65/333C08G65/332
CPCC08G65/3322C08G65/33324C08G65/33341C08G65/33396C08G81/00
Inventor 翁文桂刘超闫策姜琰琰周纯
Owner XIAMEN SINOPEG BIOTECH